Clozapine

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Abstract
Clozapine, an antipsychotic agent with relatively weak central antidopaminergic activity, displays atypical pharmacological and clinical properties vis-a-vis the classic antipsychotics. Thus, clozapine is effective against both the positive and negative symptoms of schizophrenia and has a low propensity to cause extrapyramidal effects. Furthermore, clozapine is effective in a substantial proportion (up 10 60%) of patients who are refractory to or intolerant of standard anlipsychotic therapy. Despite its promising therapeutic potential, the relatively high incidence of clozapine-induced agranulocytosis (≈1% of patients) and the associated need for regular haematological monitoring currently restricts the drug’s use to the treatment of chronic and severe schizophrenia refractory 10 standard antipsychotic therapy, and of those patients unable to tolerate such therapy. In the US, the current wholesale price of clozapine (exclusive of monitoring) is $US2.85 per 100mg tablet, amounting of $US4160 annually (1992 dollars) at the most commonly prescribed dose of 400 mg/day ($US2.40 per tablet and $US3510 annually 10 state programmes through Medicaid reimbursement legislation). In the UK, the annual cost of clozapine (at the average dose of 300 mg/day), inclusive of blood monitoring, is £1806 (1992 pounds). Although the acquisition cost of clozapine is high in comparison with that of standard antipsychotics, preliminary cost-effectiveness estimates in patients with treatment-resistant schizophrenia suggest that the clinical benefits of the drug (viz. improved psychopathology, social functioning and quality of life) may confer medium to long term economic benefits, primarily by reducing the need for psychiatric hospital services. This effect is most likely to be seen on long term (≥ 2 years) maintenance therapy with clozapine. Savings in hospital costs are, however, likely to be offset, at least initially, by increased reliance on outpatient services, and clozapine may therefore confer additional economic costs during the first year or so of treatment. In the longer term, however, the initial cost investment may be recouped in the form of savings to psychiatric institutions and insurers. Disease course and treatment outcome vary considerably in schizophrenia, a fact attributable to the probable heterogeneity of schizophrenia, and differences in patient age group and duration of follow-up. Among newly diagnosed cases, one-quarter to one-third lead to long lasting remission (with or without residual symptoms), approximately 20% have further episodes of illness with symptom-free intervals, and the remainder progress to moderate or severe chronic psychoses with marked personality changes. Schizophrenia in men is typically associated with early onset (mean age 21 years) and chronicity, whereas in women it tends to be of later onset (mean age 27 years) and to follow a remitting course. The prevalence of treatment-resistant schizophrenia ranges from 5 to 30% of patients. Frequently classified with drug-refractory patients are those intolerant of standard antipsychotics because of the development of severe extrapyramidal symptoms, and the estimated 20 to 40% of patients who develop tardive dyskinesia on long term therapy. Clinical options for the management of treatment-resistant schizophrenia are limited: common clinical practice is to increase the existing antipsychotic dose or to switch to a different class of antipsychotic. Possible adjunctive and alternative treatments include lithium, high-dose benzodiazepines, and electroconvulsive therapy. Clozapine currently appears to be the most effective antipsychotic for treatment-resistant schizophrenia and, but for its associated risk of agranulocytosis, should probably be regarded as the drug of first choice for the majority of patients. Noncomparative studies have indicated that clozapine is of significant clinical benefit in a substantial proportion (up to 60%) of patients with treatment-resistant schizophrenia, producing improvements in both positive and negative symptoms and the quality of life (including interpersonal relationships and social function) after 1.5 to 6 months of therapy, and enhanced social adaptation and a reduced need for rehospitalisation on long term (6 months to ≥ 2 years) therapy. The most pronounced improvement in psychopathology frequently occurs during the first 6 weeks of clozapine therapy, with further gradual improvement seen on maintenance therapy. Short term (6 to 8 weeks) double-blind comparative studies have provided evidence of the superior antipsychotic efficacy of clozapine (≤ 900 mg/day) versus that of chlorpromazine (≤ 1800 mg/day) in treatment-resistant schizophrenia. Although patients intolerant of standard antipsychotics generally respond better to clozapine therapy than those refractory to previous antipsychotic therapy, no reliable aetiological or clinical predictors of therapeutic response to clozapine in treatment-resistant schizophrenia have been identified. Clozapine is distinguished from standard antipsychotics by its relatively low incidence of extrapyramidal effects, of which akathisia, akinesia and tremor (≈ 6% of patients) appear to predominate over dystonia. Tardive dyskinesia has not been reported to date with long term dozapine therapy. Agranulocytosis is the most serious adverse effect of dozapine, occurrina in ≈1% of patients and requiring immediate drug discontinuation. This dyscrasia is usually of gradual onset, with maximum risk arising during the first 18 weeks of therapy; predisposing factors remain undetermined. The costs of schizophrenia to society can be divided into direct treatment costs (inpatient and outpatient care, residential care, community-based services, and drug therapy), indirect costs (lost productivity and earnings due 10 illness and/or early moratily), and intangibles (e.g. suffering experienced by the patient and family). The...